ABSTRACT Neuropsychiatric symptoms, in particular apathy, are frequently described in patients with Alzheimer's disease (AD). Apathy is a `negative' neuropsychiatric symptom that, along with blunted affect and alogia, can be prominent features of AD that are independent of cognitive impairment and mood disturbances. Negative neuropsychiatric symptoms contribute to the huge personal and economic costs of AD and are associated with substantial caregiver burden and distress. There are currently no approved treatments for these symptoms of AD. Proline is a precursor of the neurotransmitter glutamate and may function as a CNS neuromodulator. There is evidence of increased CNS and peripheral proline levels in AD, and a consequence of this may be neuromodulatory responses similar to those observed in the Prodh null mouse (the enzyme encoded by Prodh catabolizes proline), such as increased dopamine (DA) transmission. Catechol-O-methyltransferase (COMT) catalyzes deactivation of DA. Interestingly, the COMT Val158Met genotype has been associated with apathy in a clinical sample of non-demented subjects, and in patients with dementia including AD, COMT genotype has been associated with region-specific neurodegeneration that may influence behavior; thus connecting DA to neuropsychiatric symptoms of AD. We recently found that levels of fasting plasma proline and the Val158Met genotype interact, significantly predicting negative symptoms in patients with psychiatric illnesses: In COMT Val/Val patients' high proline is protective with low negative symptom severity or a greater symptom reduction over time. Patients who are carriers of the Met allele demonstrate the opposite, exhibiting significantly more negative symptoms or less symptom improvement with increasing proline. This interaction effect on negative symptoms, which we found to be consistent across two distinct psychiatric illnesses (schizophrenia and bipolar disorder) and also modifies autism spectrum symptoms, may have implications for genotype-targeted treatment, because proline-modulating medications that can either up-, or down-regulate proline already exist. We now hypothesize that COMT genotype and proline interact to modify negative symptom severity across neuropsychiatric diseases, including in AD. Specific Aims. To test for a statistical interaction between fasting plasma proline and COMT Val158Met genotype on negative neuropsychiatric symptoms in patients with probable AD. This will be achieved under the following: Aim 1a. To collect fasting blood from 126 AD patients (74 females and 52 males) who exhibit negative symptoms, and measure plasma proline plus perform COMT Val158Met genotyping. Aim 1b. To measure negative symptoms in the AD patients using the modified Scale for Assessment of Negative Symptoms (SANS-AD). Aim 1c. Use regression models to test for an interaction between COMT genotype and proline on total SANS-AD score. Impact: If COMT and proline interact on negative symptoms our findings would support genotype-targeted modulation of proline for reducing negative neuropsychiatric symptoms in AD, positively impacting quality of life.